PROJECT SUMMARY/ABSTRACT Current therapies for multiple sclerosis (MS) slow the progression of the disease but do not promote recovery. Therefore additional therapies are required to provide a CNS environment conducive for neuronal stabilization and neurorepair. Didox is a member of a unique series of polyphenol compounds that are multifaceted and have biochemical properties that have the potential to provide therapeutic benefit in MS. To test this hypothesis we conducted experiments using didox administered by injection and the chronic experimental allergic encephalomyelitis (EAE) model of demyelinating disease. We found that Didox given in this manner can prevent the onset and severity of demyelinating disease. The drug also had the ability to completely reverse the clinical symptoms of established disease. Further data associated with the EAE studies demonstrated that the production of inflammatory cytokines are reduced, leading to reduction of edema and decreased immune infiltration of immune cells into the CNS; this infiltration is normally observed in this model. The objective o this proposal is to further elucidate the therapeutic potential of Didox by evaluating its potency when given as an oral drug in a number of relevant EAE models. Oral didox will be administered by oral gavage to mice affected with either chronic EAE or relapsing remitting EAE. The drug will be given prior to the onset of disease, at the peak of disease and after the disease plateaus (in the case of chronic EAE) and prior to the onset of disease during the first remission and during the second remission in the case of elapsing remitting EAE. These two EAE models will be studied in detail before extending the same studies to two other models of MS: the chronic progressive EAE model and the secondary progressive EAE model. The kinetics of didox in the blood and CNS will be followed with a sensitive and specific HPLC/Mass spectrometry method. The ability of the drug to sustain recovery in all EAE models will be evaluated. The molecular, cellular and immunological mechanisms responsible for the drug- induced recovery will be evaluated. As noted, current therapies for multiple sclerosis mostly prevent the progression of the disease but do not reverse the symptoms of MS. In contrast Didox treatment may promote a CNS environment amenable to recovery by suppressing inflammation, preventing immune infiltration of the CNS and reducing edema, allowing clinical recovery and possibly remyelination to occur. Of additional importance, this compound has already been tested in humans, is able to traverse the blood-brain barrier of the CNS, and is tolerated well orally in other disease models. Also there is an urgent need for new oral drug therapies to arrest chronic progressive MS as well as secondary MS and preliminary studies to evaluate didox in this regard are planned. Based on our preliminary observations, we believe that didox has excellent potential to be an effective oral treatment for multiple sclerosis. It is anticipated that the results of this proposal will provide the basis for initiating clinical trial of this novel drug.